Signal transduction in a covalent post-assembly modification cascade

Pilgrim, Ben S.; Roberts, Derrick A.; Lohr, Thorsten G.; Ronson, Tanya K.; Nitschke, Jonathan R.

Abstract

Natural reaction cascades control the movement of biomolecules between cellular compartments. Inspired by these systems, we report a synthetic reaction cascade employing post-assembly modification reactions to direct the partitioning of supramolecular complexes between phases. The system is composed of a self-assembled tetrazine-edged FeII8L12 cube and a maleimide-functionalized FeII4L6 tetrahedron. Norbornadiene (NBD) functions as the stimulus that triggers the cascade, beginning with the inverse-electron-demand Diels–Alder reaction of NBD with the tetrazine moieties of the cube. This reaction generates cyclopentadiene as a transient by-product, acting as a relay signal that subsequently undergoes a Diels–Alder reaction with the maleimide-functionalized tetrahedron. Cyclooctyne can selectively inhibit the cascade by outcompeting NBD as the initial trigger. Initiating the cascade with 2-octadecyl NBD leads to selective alkylation of the tetrahedron upon cascade completion. The increased lipophilicity of the C18-tagged tetrahedron drives this complex into a non-polar phase, allowing its isolation from the initially inseparable mixture of complexes.

Citation

Pilgrim, B. S., Roberts, D. A., Lohr, T. G., Ronson, T. K., & Nitschke, J. R. (2017). Signal transduction in a covalent post-assembly modification cascade. Nature Chemistry, 9(12), 1276-1281. https://doi.org/10.1038/nchem.2839

• Journal Article Type: Article
• Acceptance Date: Jun 28, 2017
• Online Publication Date: Aug 21, 2017
• Publication Date: 2017-12
• Deposit Date: Feb 24, 2020
• Publicly Available Date: May 20, 2020
• Journal: Nature Chemistry
• Print ISSN: 1755-4330
• Electronic ISSN: 1755-4349
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 12
• Pages: 1276-1281
• DOI: https://doi.org/10.1038/nchem.2839
• Public URL: https://nottingham-repository.worktribe.com/output/4026002
• Publisher URL: https://www.nature.com/articles/nchem.2839
• Additional Information: Received: 21 February 2017; Accepted: 28 June 2017; First Online: 21 August 2017; : The authors declare no competing financial interests.